PROJECT SUMMARY Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to abstain. Extinction training has been used as a therapeutic method to reduce drug craving and relapse, although with limited efficacy due to an inability to fully capture contextual aspects unique to individual drug users. The identification of extinction-induced modifications in distinct brain circuits could lead to better neurostimulation approaches to treat drug addiction. This research studies modification of specific neural circuits by the extinction of self-administration behavior in a rat model of cocaine addiction. Our previous data indicate that extinction training enhances excitatory synaptic input to nucleus accumbens (NAc) shell neurons, and this effect attenuates psychomotor sensitization and relapse to cocaine-seeking behavior. The primary excitatory inputs to the NAc shell originate in the medial prefrontal cortex (PfC), basolateral amygdala (BlA) and ventral hippocampus (VH). Using an optogenetic low frequency stimulation approach to selectively depotentiate excitatory synaptic input emanating from these regions, this research will identify the specific source(s) of extinction-induced neuroplasticity in the NAc shell (Aim I), and study the role of this circuit-specific neuroplasticity in extinction-induced attenuation of sensitization and relapse behaviors (Aim II). Previous data also suggest that extinction of cocaine self-administration may reverse negative mood effects produced by chronic cocaine use. Thus, studies will determine the role of circuit-specific neuroplasticity in extinction- induced antidepressive efficacy (Aim III). Studies in Aim 1 will employ optogenetics to study the extinction circuits responsible for 1) extinction- induced synaptic trafficking of AMPA GluA receptor subunits, 2) extinction-induced enhancement in excitatory synaptic currents and 3) determine the direct and/or indirect NAc output neurons modified by extinction. Experiments in Aim II will determine the role of extinction-potentiated circuits in 4) extinction-induced reversal of locomotor sensitization and 5) extinction-induced attenuation of context- and cocaine-primed reinstatement of cocaine-seeking behavior. Experiments in Aim III will investigate the role of extinction-specific neuroplasticity in reversing negative mood effects in tests of 6) dysphoria in cocaine-conditioned place aversion, 7) learned helplessness/behavioral despair in forced swim tests and 8) anhedonia in sucrose preference tests. The integration of these neurobiological and behavioral datasets will determine the significant role that circuit-specific neuroplasticity plays in the beneficial effects of extinction on motivational and mood disturbances that contribute to cocaine addiction. A clear delineation of limbic circuits that mediate such beneficial effects could lead to better behavioral and targeted neurostimulation approaches in the treatment of cocaine and other addictions.